Neurodegenerative diseases such as amyotrophic lateral sclerosis (ALS), Alzheimer’s, and Parkinson’s are devastating and often futile maladies, that cause tremendous physical, emotional, and economical burden on patients and their families. Over a century of study has yielded a moderate understanding of these diseases, but insufficient to effectively treat them. The last few decades, however, have revealed an immune revelation whereby genetics, pre-clinical animal models of disease, and epidemiological studies point to a dysfunctional immune system as a major contributor to disease initiation and progression. A personal connection to multiple neurodegenerative diseases led to my training in a combination of genetics, neuroscience, and immunology. Predictably biased, I was confident that immune-modulating therapies were the next transformative therapies, which led me to seek out mentors and projects that could quickly translate findings into the clinic. Our group and others ride a culminating wave ready to break with meaningful therapies for many of these diseases.
This past year’s pandemic is evidence that the immune system is extremely complicated, compounded by factors such as aging patient populations, genetic diversity, and environmental exposures. Nonetheless, the resounding similitude within patients from ALS and across the neurodegenerative disease spectrum, is that their intricate immune systems are dysfunctional compared to the average (what we refer to control) population. Gaining a deep understanding of this immune dysfunction within the neurodegenerative diseases has been a focal point of research in the last few decades and we are optimistic in translating these findings into viable therapeutics that can benefit a population that has been waiting far too long for hope.
What have we concluded regarding the research on the immune dysfunction in ALS, Alzheimer’s, Parkinson’s, and more? Well, it is evident that there is a pro-inflammatory fire that begins early in the disease and worsens with disease progression. The initiating and sustaining factors behind this fire are debatable, but what we do know (documented by our team and other groups) is that it creates an overwhelmingly toxic environment not suitable for healthy neurons, which inevitably leads to their degeneration. The pinnacle finding from our team was that a population of firefighting immune cells known as regulatory T cells (Tregs) had lost their ability to do a very important job--to extinguish the pro-inflammatory immune fires in these diseases. Since this discovery, we have been developing methods and strategies for restoring Treg function so that they could effectively put out the inflammatory fires within patients in order to slow or halt the progression of disease.
The formidable task and question at hand is how to design therapies treating complex diseases involving dysfunctional immune systems, particularly at a point when the inflammatory fire appears out of control? Our intricate immune systems have evolved to include overlapping and redundant mechanisms to ensure activities are carried out; a crucial component to resolving and clearing an infection or injury. The same redundancies that benefit us also make many inflammation-targeting pharmaceuticals difficult to repurpose effectively for neurodegenerative diseases as they typically target single mechanisms and/or pathways in inflammatory cascades. Utilizing an approach that harnesses an immune cell’s multitude of mechanisms was intriguing and the basis of our approach.
What if we “fix” the Treg cells to be functional again and used them to fight the inflammatory fire within patients with neurodegenerative diseases? Years of optimizing GMP protocols and manufacturing has culminated in the ability to remove dysfunctional Tregs from patients with ALS and generate an army of highly suppressive and anti-inflammatory Tregs to be infused back into the patients to fight the inflammatory fires. Preliminary data shows this method is well tolerated in ALS patients receiving the infusions and even shows halting the fast decline typically seen in ALS patients; a non-trivial feat for any neurodegenerative disease much less ALS. This is an exciting finding with many more patients enrolled in a subsequent trial to further examine the effectiveness of this type of treatment. Stay tuned for trial results and what comes next!